New anthelmintic agents

ABSTRACT

New 1-(2-arylvinyl) and 1-(2-arylacyl)-pyridinium and Alpha picolinium salts and their use as anthelmintic agents.

United States Patent McFarland [54] NEW ANT HELMINTIC AGENTS [72] Inventor: James W. McFarland, Lyme, Conn.

[73] Assignee: Chas. Pfizer &Co., Inc., New York,

[22] Filed: April 24, 1970 [21] Appl. No.: 12,552

Related US. Application Data [60] Division of Ser. No. 675,285, Oct. 16, 1967, Continuation-impart of Ser. No. 560,856, June 27, I966, abandoned.

3,311,618 3/1967 Heseltine et a1. ...260/240.8 X

[ 3,684,802 [451 Aug. 15,1972

FOREIGN PATENTS OR APPLICATIONS 682,255 10/1939 Germany ..260/240 D 1,543,985 9/ 1968 France ..260/240 D OTHER PUBLICATIONS King et al., J. Am. Chem. Soc., Vol. 72, pages 2507 to 2508 (1950) Chemical Abstracts I, Vol. 4, p. 7414 (1910) Chemical Abstracts 11, Vol. 63, C01. 18026 (1965) (Abstract of Doolittle et al.)

Primary Examiner-John D. Randolph Attorney--Connolly and Hutz [57] ABSTRACT New I-( 2-arylvinyl) and l-(2-arylacyl)-pyridinium and a-picolinium salts and their use as anthelmintic agents.

1 Claim, No Drawings isothiazolyl,

1 NEW ANTHELMINTIC AGENTS CROSS-REFERENCE TO RELATED APPLICATION The instant application is a division of application Ser. No. 675,285 as filed Oct. 16,1967 which in turn is a continuation-in-part of copending application Ser. No. 560,856, filed June 27, 1966 and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to certain compounds which have been found to possess valuable therapeutic properties. More particularly, this invention relates to l- (2-arylvinyl)-pyridinium and a-picolinium salts and to l-arylacylpyridinium and a-picolinium salts which are valuable in the control of helminthiasis in animals including pinworrn and hookworm diseases.

Helminthiasis, the infestation of the animal body by various species of parasitic worms, is a very common and wide spread disease ali'ecting household and farm animals in all parts of the world. The economic significance of this disease is well known and has been the cause of extensive research on the control of helrninthic parasites for many years. The effectiveness of the drugs used has not been entirely satisfactory for many reasons; e.g., limited anthelmintic spectrum, specificity of action, high cost and low activity.

SUMMARY OF THE INVENTION The new and novel compounds of this invention are of the formula:

where Y is 2-thiazolyl, 4-thiazolyl, S-thiazolyl, 4- isothiazolyl, 4-methyl-5-thiazolyl, 3-methyl-4- 3-pyrazolyl, 4-methyl-3-pyramlyl, methyl-4-pyrazolyl, 4-methyl-5-oxazolyl, 2-pyrrolyl, lmethyl-2-pyrrolyl, 3-methyl-2-thienyl, 3-ethyl-2-thienyl or 3-halo-2-thienyl where halo is chloro, bromo or iodo, R is hydrogen or methyl; and X is a compatible anion.

Another aspect of this invention involves the discovery that certain known compounds, homologues, positional isomers or analogues of known compounds are unexpectedly effective anthelmintic agents. These compounds are of the above formula but where Y is 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-methyl-2-furyl, phenyl, Z-methylphenyl, 2-ethylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methyl- 2-thienyl, 3-ethyl-2-thienyl, 2-methyl-3-thienyl, 2- halophenyl where halo is chloro, bromo, fluoro or iodo, or 3-halo-2-thienyl where halo is chloro, bromo or iodo; R is hydrogen or methyl; and X is an anion of a pharmacologically-acceptable salt.

Also contemplated in this invention are I-( Z-hydroxy-Z-arylethyl) pyridinium and a-picolinium salts which are valuable intermediates. These compounds have the formula:

where Y is Z-thiazolyl, 4-thiazolyl, S-thiazolyl, 4- isothiazolyl, 4methyl-5-thiazolyl, 3-methyl-4- isothiazolyl, 3-pyrazolyl, 4-methyl-3-pyrazolyl, 3- methyl-4-pyrazolyl, 4-methyl-5-oxazolyl, l-methyl-Z- pyrrolyl, 2-pyrrolyl, Z-methylphenyl, 2-ethylphenyl or 3-halo-2-thienyl, where halo is chloro, bromo or iodo; R is hydrogen or methyl and X is a compatible anion.

Still another aspect of this invention involves the discovery that several known compounds, homologues or positional isomers of known compounds are effective anthelmintic agents. These compounds are of the 5 formula:

where Y is Z-thienyl, 3-thienyl, Z-furyl, 3-methyl-2-furyl, phenyl, 2-hydroxypheny1, B-hydroxyphenyl, 4- hydroxyphenyl, 3-methyl-2-thienyl, 3-ethyl-2-thienyl, 2-methyl-3-thienyl, 2-halophenyl where halo is chloro, bromo, iodo or fluoro; R is hydrogen or methyl; and X is an anion of a pharmacologically acceptable salt.

DETAILED DESCRIPTION OF THE INVENTION The new and novel compounds of this invention are prepared according to the following sequence:

Light ll Y-C-CHzI where X is chlorine, bromine or iodine,

where Y, X and R are as aforesaid.

The aryl methyl ketones are halogenated to form the a-iodo, a-chloro or a-bromo compound by any of several known methods, such as reacting chlorine with the ketone in the presence of light, by reacting the ketone with cupric bromide, or by reacting the ketone with iodine. On the basis of economy and convenience the chloro and bromo compounds are preferred starting materials.

The pyridinium or a-picolinium salt of the ketone is prepared by reacting cupric bromide suspended in an organic solvent such as ethyl acetate with a chloroform solution of the ketone. The chloroform solution is preferably added dropwise to the refluxing suspension of cupric bromide to avoid too rapid an evolution of hydrogen bromide. The mixture is cooled to room temperature, the cuprous bromide is filtered from the mixture, the solvents are evaporated under reduced pressure and the oily residue of the crude a-bromoketone is taken up in chloroform. To the chloroform solution is cautiously added a molar equivalent amount and preferably an excess to ensure complete reaction of pyridine or a-picoline. An exothermic reaction results. Generally, the products crystallize after the reaction solutions cool. The resulting pyridine or a-picoline salt may be recrystallized from methanol or the like. To an aqueous solution of the product is added a V4 to molar equivalent of sodium borohydride. The mixture is allowed to react at room temperature with stirring. The water is evaporated and the resulting alcohol may be recrystallized from alcohol solvents such as isopropanol and methanol. The alcohol product is dehydrated by heating it under reflux with a dehydrating agent such as an excess of benzoyl chloride, acetic anhydride/acetic acid mixture or by heating it in an autoclave at 220 C. with acetic anhydride and hydrochloric acid. While other reagents such as phosphorous pentoxide and tosyl chloride are effective, greater yields are obtained by the previously mentioned reagents. Benzoyl chloride is reacted with the alcohol at high temperatures, preferably at about 190 C. in a wax bath or the like, for about one hour or longer depending of course on the particular compound in question. The alcohol, acetic anhydride and hydrochloric acid are heated in an autoclave at about 220 C. for 1 hour or longer. After the dehydration is complete, the solvents and reagents are evaporated and the residue is taken up in acetone or acetone and water or a similar solvent. The resulting l-(2-arylvinyl) pyridinium bromide crystallized as the solvent mixture cools.

The chloride salt is prepared in the same manner starting with the a-chloro ketone. Other salts such as the monostearyl fumarate and the hexafluorophosphate, are prepared by reacting the arylvinylpyridinium or picolinium bromides or chlorides with the corresponding acids or their alkali metal salts, either at room temperature or at elevated temperature. Altemately the bromide salt may be converted to the chloride salt by treating a dilute aqueous solution of the bromide with an ion-exchange resin such as Amberlite IRA 400, 401 or 410 in the chloride cycle. Amberlite is a trademark of the Rohm and Haas Company. Other similar ion-exchange resins familiar to those skilled in the art may also be used.

The compatible anions of the salts of this invention are those prepared from aqueous acid solution a pH less than 9. The compatible anions include both pharmacologically-acceptable anions and those which are not pharmacologically-acceptable. The pharmacologically-acceptable anions are those formed from pharmaceutically-acceptable, salt-forming acids which do not substantially increase the toxicity of the base compound. The anions which are of particular value in therapy are those formed from hydrochloric, hydriodic, hydrobrornic, phosphoric, metaphosphoric, nitric, sulfuric, acetic, citric, tartaric, succinic, hexafluorophosphoric, monostearyl fumaric acids and the like. Compatible anions which are not pharmacologically-acceptable are those formed from such acids as perchloric and hydrofluoric. These anions, while not useful in therapy, are valuable for isolation and purification of these newly recognized biologically-active compounds. Furthermore, they are useful for the preparation of pharmacologically-acceptable salts.

A specific embodiment of the process of this invention as it relates to the control of helrninthiasis comprises administering the compounds to subjects by the oral or by the parenteral route. In the treatment of helminthic infection, the oral route is preferred. An oral dose of from about 5 to 300 mgJkg. is recommended. Ordinarily, a single dose is sufficient but in the event multiple doses are employed, this dose may be repeated on 2 or 3 consecutive days. The oral route may be employed by mixing the effective ingredient with an emulsifying agent and employing a drench solution which is squirted down the throat so that the recommended level is reached in the animal.

Tablets, capsules and boluses can also be used to contact the effective ingredient with the parasites within the animal. In this case, the usual dose range is from A; to 15 grams for animals weighing from 30 to 1000 pounds. The tablets, capsules and boluses are prepared by conventional means.

Dry mineral salt mixtures containing the l-(2-arylvinyl)pyridinium salts, l-(2arylvinyl) a-picolinium salts, l-arylacyl pyridinium salts or the l-arylacyl-a-picolinium salts are prepared containing from 0.1 to about 5.0 percent of the active ingredient mixed with salt (sodium chloride) and other minerals with which it is desired to treat the animal. These mixtures are fed on an ad libitum basis by adjusting the proportion of active ingredient in the mixture to the average daily consumption per animal so as to provide the proper daily dose as specified above.

The material can also be supplied to the animal by mixtures of 0.002 to about 5.0 percent of the compound admixed with feed. The daily dose of anthelmintie is usually mixed with only a portion of the animals daily allotment to insure complete consumption of the dose.

It should be noted that the compounds may be administered either alone or in combination with pharmaceutically-acceptable carriers and diluents in both single and multiple dosages. For purposes of oral ad ministration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate are used. .Bonding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia together with disintegrants such as starch, alginic acid and certain complex silicates may be used. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in soft elastic and hard-filled gelatin capsules. Preferred materials include lactose and high molecular weight polyethylene glycols. When aqueous suspensions are desired, the essential active ingredient is combined with emulsifying and/or suspending agents, together with such diluents as ethanol, propylene glycol, glycerine and various like combinations thereof.

For parenteral administration, solutions or suspensions of the salts in methyl stearate or other completely saturated vegetable oils may be employed. Aqueous solutions of the water-soluble compounds may also be used for parenteral administration. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent rendered isotonic with sufficient saline or glucose.

EXAMPLE I l-[2-( 3-Methyl-2-thienyl )vinyl] pyridinium Bromide A. 1-(3-Methyl-2-thenoylmethyl) pyridinium Bromide A suspension of 223 grams (1.0 mole) of cupric bromide in 400 ml. of ethyl acetate is vigorously stirred and heated under reflux, while a solution of 85.3 grams (0.6 mole) of methyl 3-methyl-2-thienyl ketone in 400 ml. of chloroform is added dropwise over a period of 30 minutes. The dark green solids of the reaction mixture change to nearly white over a period of 90 minutes, with vigorous evolution of hydrogen bromide. After cooling the mixture to room temperature, the cuprous bromide is filtered from the reaction mixture and the filtrate is evaporated under reduced pressure, to an oily residue which is taken up in 300 ml. of chloroform. The chloroform solution is filtered to free it of small amounts of insoluble material, and is then placed in a round-bottom flask equipped with a reflux condenser. Pyridine (94.3 grams, 1.2 mole) is added, and an exothermic reaction ensures. After stirring and cooling, the oil which forms crystallizes. After standing overnight at room temperature, the mixture is filtered and washed with chloroform to furnish 127.2 grams, (85 percent of theory) of l-(3-methyl-2-thenoylmethyl) pyridinium bromide, m. p. 250-25l C. Recrystallization from methanol yields a l-(3-methyl-2-thenoylmethyl) pyridinium bromide melting at 259261C. Anal. Calcd. for C H Br NOS (298.72): C, 48.32; H, 4.06, N, 4.70. Found: C, 48.29; H, 4.12, N, 4.44. B. l-[2-Hydroxy-2-(3-methyl-2-thienyl) pyridinium Bromide A stirred solution of 44.7 grams (0.15 mole) of 1-( 3- methyl-2-thenoylmethyl) pyridinium bromide in 200 ml. of water is treated portionwise with 1.7 grams (0.045 mole) of sodium borohydride. The product begins to precipitate immediately upon addition of the ethyl] hydride. After the final addition, the mixture is cooled in an ice bath; the product is filtered, washed with icecold water, and dried in a steam oven at 65ovemight. The yield is 41.2 grams, 91 percent of theory of a yellow-brown solid mp. 219 C. (dec. When the product is recrystallized twice from water, colorless crystals of 1-[2-hydroxy-2-(3-methyl-2-thienyl) ethyl] pyridinium bromide, m.p. 202-203 C. (dec. are obtained.

Anal. Calcd. for C H Br NOS (300.23): C, 48.00; H, 4.70; N, 4.67. Found: C, 48.21 H, 4.69; N, 4.60. C. 1-[2-( 3Methyl-2-thienyl)vinyl] pyridinium Bromide To a 2-liter, 3-neck, round-bottom flask, equipped with a mechanical stirrer, reflux condenser and thermometer is added 0.6 mole of 1-[2-hydroxy-2-( 3- methyl-2-thienyl)ethyl] pyridinium bromide and 600 ml. of benzoyl chloride. The mixture is heated at 110 C. for 10 minutes and then the temperature is slowly raised to 150 C. whereupon much foaming occurs. The temperature is raised to 180 C. and maintained at that temperature for one hour. The mixture is cooled to C. and placed in an ice bath for several hours. The product is filtered, washed with acetone and air dried. Recrystallization from acetone/methanol produces a material melting at 231-232 C. Anal. Calcd. for C H BrNS, C, 51.07; H, 4.29; N, 4.96. Found: C, 50.92; H. 4.40; N, 4.71.

EXAMPLE II 1-[2-( 2-Thienyl)vinyl] pyridinium Bromide Monohydrate:

A 2-liter, round-bottom flask, equipped with a mechanical stirrer, reflux condenser and thermometer, is charged with 180 grams (0.632 mole) of 1-[2- hydroxy-2-(2-thienyl)ethyl]pyridinium bromide and 600 ml. of benzoyl chloride. The mixture is heated at C. for 10 minutes and then the temperature is slowly raised to C. whereupon much foaming occurs. After the foaming subsides (about 20 minutes), the temperature is raised to 180 C. and maintained there for 1 hour. The mixture is cooled to 80 C., and placed in an ice-bath for several hours. The dark crystalline product is filtered, washed with acetone and air-dried. The yield is 120 grams m.p. -l65 C. Further recrystallization from acetone/methanol (8.3 produces no improvement in the melting point range.

The monohydrate is prepared by adding 594 grams of recrystallized product obtained from several runs, to 800 ml. of water, adding activated carbon and filtering. The bright yellow filtrate is poured into 8 liters of ab solute ethanol and stored at -30 C. for three hours. The crystals which form are filtered from the solution, washed with ether and air-dried overnight. The melting point of the product depends to a considerable extent on the technique employed. Generally, some melting at 98l00bL C. is observed, but it is also possible to observe nothing until the melting point of the anhydrous material is obtained, i.e. -181 C.

Anal. Calcd. for C H BrNS'H O (286.1 1

C, 46.18; H, 4.23; N, 4.89; Br, 27.93. Found:

C, 45.99; H, 4.35; N, 4.89; Br, 28.13.

EXAMPLE 111 1-[ 2-Thienyl )vinyl ]pyridinium Hcxafluorophosphatc A solution of 286 grams (1.0 mole) of l-[2-(2-thienyl)vinyl]pyridinium bromide monohydrate in 3,000 ml. of water is mechanically stirred at room temperature, while 224 grams (1.0 mole) of a 65 percent aqueous solution of hexafluorophosphoric acid is added in a steady stream over a period of one minute. The resulting precipitate is filtered, washed with water and with ethanol. The wet cake is taken up in a hot solution of 10 liters of absolute ethanol and 3 liters of acetone. Insoluble material is filtered and the filtrate is concentrated to about 9 liters volume whereupon crystals begin to form. The filtrate is cooled to 0 C. and the resulting crystalline product is filtered, washed with absolute ethanol and with hexane. The air-dried product weighs 270 grams, m.p. 182183 C. Analytically pure material is obtained by recrystallization from a mixture of acetone and absolute ethanol followed by recrystallization from acetonitrile/ethyl acetate. The product melts at l78.5-1l81.0C.

Anal. Calcd. for C H F NPS (333.25 C, 39.64; H, 3.03; N, 4.20. Found: C, 39.67; H, 3.13; N, 4.24.

EXAMPLE IV 1 [2-( 2-thienyl )vinyl ]pyridinium Monostearyl Fumarate Dihydrate A mixture of 2.86 grams (0.01 mole) of l-[2-(2-thienyl)vinyl]pyridinium bromide monohydrate, 50 m1. of water and 3.91 grams (0.01 mole) of sodium monostearyl fumarate is stirred for 2 hours at room temperature. During the course of the reaction the in- EXAMPLE V 1-(2-(4-methyl-5-oxazolyl)vinyl]a-picolinium Bromide This compound is prepared from methyl 4-methyl-5- oxazolyl ketone according to the procedure of Example 1, parts B to D, by substituting a-picoline for pyridine.

EXAMPLE VI l-[ 2-(4-methyl-5-oxazolyl)vinyl ]pyridinium Bromide This compound is prepared from methyl 4-methyl-5- oxazolyl ketone according to the procedure of Example I, starting with part B.

EXAMPLE VII The compounds of Table l are prepared according to the procedure of Example I. The ketone intermediates are prepared according to part A. The hydroxy intermediates are prepared according to part B by reducing the keto group. The vinyl products are obtained according to part C.

TABLE I Starting material Product 1-(2-acylvinyl) pyridinium bromide 4-acetylthiazole S-acetylthiazole 4-acetylisothiazole 4-motl1ly-fi-acctylthiazolo B-nwLhyl-l-acctylisothiazole 3-ncotylpyrumlu -()ll H-N lir- H H Hung-0 mm Starting material Product 4-methyl-3-acetylpyrazole I CH3 CH=CHI\ Br- N) CH:

3-methyH-acetylpyrazole CH CH=OHN Br- N CHa 2-acety1pyrrole l CH=CHN Brl H CH3 l-methyl-Z-acetylpwrole H l CH-CH s B K \N/ r l I CH3 CH3 4-rnethyl-5-acetyloxazole 1,;

i i 6 l O CH CH Br- EXAMPLE IX C. 1-[2-(2-Thienyl)vinyl] pyridinium Chloride Dihydrate 1-[2-( Z-Thienyl )vinyl]pyridinium Chloride Dihydrate A. 1-(2-Thenoylmethyl) pyridinium Chloride A solution of 30.0 g. (0.187 mole) of chloromethyl Z-thienyl ketone, prepared according to the procedure of W. S. Emerson and T. M. Patrick, Jr., J. Org. Chem., 13, 722-8 (1948), and 100 ml. of chloroform was treated with 30 ml. (0.38 mole) of pyridine.

The resultant solution was heated under reflux for minutes, allowed to cool to room temperature, and then cooled further in an ice bath. The resultant crystalline product was filtered to yield 27.1 g. (63 percent of theory) of the desired pyridinium ketone: m. p. 9498 C. (softened at about 60 C.). Recrystallization is from acetone/methanol for analysis, the product weighed 16.7 g., m. p. 94-97 C.

Anal. Calcd. for C H ClNOS (239.73

C, 55.1 I; H, 4.21; N, 5.84. Found:

C, 54.39; H, 4.32; N, 5.64.

B. 1-[2-Hydroxy-2-(2-thienyl)ethyl]pyridinium Chloride A solution of 16.0 g. (0.067 mole) of 1-(2-thenoylmethyl) pyridinium chloride in 100 ml. of water was treated portionwise with 0.84 g. (0.0233 mole) of sodium borohydride. After stirring for minutes at room temperature, the aqueous solution was evaporated under reduced pressure to yield a solid residue which was recrystallized from isopropanol/methanol afiording 7.3 g. (45 percent of theory) of the desired product: m.p. 2 l 8-219C. The product was recrystallized again to yield 5.1 g. of product, m.p. 219-220.5C.

Anal. Calcd. for C H ClNOS (241.75): C, 54.65; H, 5.01; N, 5.79. Found: C, 54.55; H, 5.08; N, 5.62.

A solution of 50.8 g. (0.21 mole) of l-[2-hydroxy-2- (Z-thienyl) ethyl] pyridinium chloride and 125 ml. of benzoyl chloride was heated cautiously to 190 C. and held at that max: for an hour. After cooling somewhat, the solution was concentrated by distilling most of the excess benzoyl chloride from the mixture under reduced pressure. The pot residue was triturated with acetone and ether to yield 39.0 g. of crude, darkbrown, crystalline material: m.p. 5358 C. The crude product was recrystallized from a hot solution of acetone and water to effect solution. Cooling to room temperature and subsequent cooling to 05 C. gave 16.8 g. of bright yellow crystals: m.p. 6566 C; A (methanol) 240 m p. (9400), 265 my. (10,000), 353 my. (616,000). Anal. Calcd. for C H Cl NS-2H,O (259.76): C, 50.86; H, 5.43; N, 5.39; Cl, 13.65. Found:

C, 50.96; H, 5.50; N, 5.76; Cl, 13.98.

EXAMPLE x l-[2-(2-Thienyl)vinyl]a-picolinium Bromide A. 1-[2-hydroxy-2-(2-thienyl)ethylla-picolinium Bromide A solution of g. (0.2 mole) of l-(2-thenoyl- 60 methyl) a-picolinium bromide, prepared according to the procedure of Examples I and V1, and 300 ml. of water is heated with 2.26 g. (0.06 mole) of sodium borohydride in the manner of part C, Example 1. The product is filtered, washed with water, and is recrystallized from isopropanol to yield 1-[2-hydroxy-2-(2-thienyl) ethyl]a-picolinium bromide: m.p. 191192 C. Anal. Calcd. for C H Br NOS (300.23):

C, 48.00; H, 4.70; N, 4.67. Found: C, 47.76; H, 5.04; N, 4.30. B. 1-[2-( 2-Thienyl)vinyl]a-picolinium Bromide A mixture of 7.5 g. (0.025 mole) of the hydroxy compound of part A, and 20 ml. of benzoyl chloride is treated in the manner of part D, Example 1. The crude crystalline product is recrystal-lized from isopropanollmethanol to yield 1-[2'-(2-thienyl)vinyl]apicolinium bromide: m.p. 188-l 89C.; max (11,0) 268 mp.(1l,300329 my. (1 1,200). Anal. Calcd. for C,,H,,Br NS (282.22); C, 51.07; H, 4.29; N, 4.96. Found: C, 51.14; H, 4.26; N, 5.01.

EXAMPLE X1 1 2Methylstyryl pyridinium Bromide A. 1-(B-Hydroxy-Z-methylphenethyl) 1 pyridinium Bromide A solution of 80.3 g. (0.274 mole) of l-(2- methylphenacyl) pyridinium bromide, prepared according to the procedure of J. W. Baker, J. Chem. Soc., 445, (1938), and 400 ml. of water is treated with 3.36 g. (0.091 mole) of sodium borohydride in the manner described in part C, Example I. The product is filtered, washed with water and recrystallized from ethanol to yield l-(/3-hydroxy-2-methylphenethyl) pyridinium bromide: m.p. 251-253 C. Anal. Calcd. for C H Br NO (249.20): C, 57.15; H, 5.48; N, 4.76. Found: C, 57.34; H, 5.27; N, 4.66 B. l-(2-Methylstyryl) pyridinium Bromide A mixture of 15.0 g. (0.05 mole) of the hydroxy compound of part A and 20 ml. of benzoyl chloride is treated in the manner of part D, Example 1. The crude crystalline product is recrystallized from acetone/methanol to yield l-(2-methylstyryl) pyridinium bromide; m.p. 188-190 C.; )lmax. (11,0) 229 mp. (61 1,100; 318 My. (e12,400). Anal. Calcd. for C H Br N (276.18): C, 60.88; H, 5.1 l; N, 5.07. Found: C, 61.08; H, 5.07; N, 4.89.

EXAMPLE XII The arylvinyl pyridinium and a-picolinium salts were administered, at the levels indicated, to mice infected with N. dubius, H. nana, N. muris and S. obvelata. The ratio of the number of mice cleared of the parasite to the number of mice infected, as shown in the table, indicates that the listed compounds are effective anthelmintic agents.

TABLE 111 Compound Dose Mi m.gl kg. No. Cleared/N0. Infected 1: days N. S. H. N. Dubl'us obvelala nana muris l -[2-(2-Thieny1)vi- 200 X 1 4/4 4/4 /4 nyl] pyridinium 50 X 1 4/4 4/4 0/4 Chloride Dihydrate 12.5 X 1 3/4 0/4 0/4 1-[2-(2-Thienyl )ui- 200 x 1 4/4 4/4 0/4 y l pyridiniumv 50 X 1 8/8 4/8 0/4 2 4 Bromide Monohydrate 12.5 X 1 3/8 0/8 0/8 0/4 1-[2-(2-Thienyl)vi- 100 X 1 4/4 0/4 0/4 nyl] pyridinium 25 X 1 3/4 0/4 0/4 Hexafluorophosphate 6.25 X l 114 0/4 0/4 u u n x 3 l 25 X 3 5/8 1-[2- (2-Thienyl)ui-. 62.5 x 1 3/4 0/4 0/4 nyl] pyridinium 31.25 X 1 2/8 0/4 0/4 Monostearylfumarate Dihydrate 15.125 x 1 1/12 0/4 0/4 50x3 7 5 12.5 x 3 0/4 1-[243-me1h 1-2- 62.5 x 1 8/8 0/8 0/8 thienyl)vinyl] pyr- 15.125 X 1 11/12 4/12 0/12 idinium Brolmde 7.8 X 1 3/4 125 x 3 3/3 1 31.25 x 3 7/8 15.125 x 3 014 I0 l-[2-(2thieny1)vi- 250 X 1 2/2 0/2 0/2 nyl] oi-picolinium 125 X 1 4/4 1 0/4 0/4 Bromide 31.25 x 1 0/4 0/4 0/4 l-Styrylpyridinium 125 X 3 4/4 4/4 0/4 3/4 Bromide 62.5 x 3 4/12 0/12 0/12 31.25 x 3 0/4 l-(2-rnethylstyryl) 250 x 1 3/3 3/3 0/3 2/2 15 pyridinium Bromide 62.5 X 1 3/4 4/4 0/4 1/4 1-(3-hydroxystyryl) 250 x 3 4/4 4/4 0/4 pyridinium Bromide 250 X 1 2/4 4/4 0/4 Dihydrate 62.5 x 1 0/4 0/4 0/4 l-[2-(2-t'uryl)vinyl] 250 x 3 3/3 3/3 0/3 pyridinium bromide 250 X 1 2/4 0/4 0/4 EXAMPLE X111 The ketone pyridinium and a-picolinium salts of Table IV were administered, at the levels indicated, to

mice infected with N. dubius, H. 113113, N. muris and s. obvelata. The ratio of the number of mice cleared of the parasite to the number of mice infected, as shown in the table, indicates that the listed compounds are effective anthelmintic agents.

TABLE IV Compound Dose MicemgJrg. No. Cleared/No. infected x days N. S. H.

Dubiur obvelata nana muris 1-(2-thenoylmethyl) 1000 X 3 0/4 0/4 4/4 pyridinium Iodide 500 X 3 0/3' 0/3 3/3 200 x 3 0/4 0/4 0/4 l-Phenacylpyridinium 500 X 3 0/4 0/4 3/4 Bromide 250 x 3 013 0/8 s/s 125 x 3 0/4 0/4 0/4 l-Salicyloylmethyl- 500 X 1 3/8 0/8 0/8 pyridinium Bromide 250 x 1 4/8 0/1; 0/8 125 x 1 0/4 0/4 0/4 500 x 3 6/8 250 x 3 4/8 125 x 3 us 1-(3-methyl-2-thenoyl- 125 x 1 4/4 0/4 0/4 methyl) pyridinium 62.5 x 1 81s on; 0/8 Bromide 31.25 x 1 1/4 0/4 0/4 l-(Z-Methyl henacyl) 250 x 3 4/4 0/4 0/4 3/4 pyridinium romide 250 x 1 4/4 0/4 0/4 1/2 EXAMPLE XIV The ketone intermediates of the products of Exam ples VII and VII] which have the formulas:

Y-1:oH,-i{ Brand o where Y is Z-thiazolyl, 4-thiazolyl, S-thiazolyl, 4- isothiazolyl, 4-methyl-5-thiazolyl, 3-methyl-4- isothiazolyl, 3-pyrazolyl, 4-methyl-3-pyrazolyl, 3-

methyl-4-pyrazolyl, Z-pyrrolyl, l-methyl-2-pyrolyl, 4-

methyl-S-oxazolyl, 2thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, phenyl, 2- methylphenyl, 2-hydroxyphenyl, B-hydroxyphenyl, 4- hydroxyphenyl, 2-chlorophenyl, 2-bromophenyl, 2- iodophenyl or 2-fluorophenyl, are found to be effective anthelmintic agents when tested according to the procedure of Example XIII.

When the sulfate, phosphate chloride, iodide, citrate, tartrate, hexafluorophosphate, monostearyl fumarate, acetate, and succinate salts are substituted for the bromide salt, they are found to be effective anthelmintic agents.

EXAMPLE XV When the pyridinium and B-picolinium bromides listed in Table V are tested according to the procedure of Example XII, they are found to be effective anthelmintic agents.

Ar cH=cH QB; U liil 2-thlonyl- Z-Iuryla-thlonyl li-luryll N l l 2-thlazolyl b-pyruwlyl- N m J l N Ly 4-thlazolylphenyl- IU T 4-isothlazolylz-hydroxyphenyl H OH S-pyrazolyl- 3-hydroxyphenylon, y

l J CH:

Z-methyl-B-thlenyl .tmstlx l-fihlenyl 4-molhyl-5-thlnmlyl l-mothyl-2-pyrrolyllFl when the sulfate, phosphate, chloride, iodide, citrate, tartrate, hexafluorophosphate, monostearyl fumarate, acetate, and succinate salts are substituted for the bromide salt, they are found to be effective anthelmintic agents.

EXAMPLE XVI Acutely infected dogs containing vover 500 hookworm oval gram were fasted overnight and dosed orally with l-[2-( 2-thienyl)vinyl] pyridinium hexafluorophosphate at a level of 25 mg./kg. Food was withheld for another two hours and post-treatment fecal samples are obtained not less than 72 hours later and the ova counts are determined. The activity is based on percent reduction of ova burdens in faces. At the indicated level hookworm ova were reduced by more than percent.

Following the same procedure, hookworm ova were reduced by more than 90 percent when 25 mgJkg. of l- [2-(2-thienyl)vinyl] pyridinium bromide monohydrate was administered to infected dogs.

EXAMPLE XVII Eighteen pigs, 3 to 4 weeks old were evenly divided by a random process among 6 pens on the basis of weight, sex and thriftiness. A standard pig diet containing respectively, 100, and 50 grams per ton of Terramycin, Neomycin sulfate and penicillin was fed to the animals. Medication, as indicated in Table VI, was administered in water drench by stomach tube for four consecutive days. The pigs, except for the negative control pigs, were infected with a dose of 4 X 10 larvated ova of Ascaris suum on the second and third days of medication. The dosages administered were determined from the weights of the first day of the test. The pigs gained an average of 1.1 kg. during the 4-day period of medication, thus the true dose rate is slightly less than indicated. The results of this experiment are given in Table VI. These results show that the compounds are very effective anthelmintic agents.

TABLE VI Treatment Pigs Lesion Lesion Ascaris Count- Score- Laura: Liver (1) Lung (2) Count (3) Non-medicated 3 0.66 1.0 0.0 Unif. Controls Non-medicated 3 42.66 3.0 2861.66 Infected Controls 1 Compound A 3 [.00 0.0 2.5 20 mg./kg. Compound A 3 0.0 1.0 0.0 100 mgJkg. Compound B 3 6.33 L33 6.66 8 mgJkg. Compound B 3 0.50 0.50 0.0 40 mgJkg.

A is l-( Z-methylstyryl) pyridinium Bromide. Compound B is l-[2-(3-methyl-2- thienyl)vinyl] pyridinium Bromide.

(1) Average number of Ascaris lesions in 6 sq. cm. on the dorsal aspect of the left central lobe.

(2) Average score by the method of Brown and Chan., Am. J. Vet. Res., l6,0ct. 1955;6/3.

(3) Number of larvae recovered from 10 grams of lung tissue.

EXAMPLE XVIII The l-[2-hydroxy-2-(aryl)ethyl] B-picolinium and pyridinium salt intermediates listed in Table VII are prepared according to the procedure of Example I, part C; Example IX, part B; and Example XI, part A, by reduction of the ketone intermediate.

TABLE VII HYDROXY INTERMEDIA'IES O H (})H J, F? Y- H -CHzI X Y--CH-CH2-I\ X- l. R

Y R X- 2-thiazolyl I-I Cl Z-thiazolyl CI-l, Br 4-thiazolyl CI-l, PF. 4-thiaz'olyl I'I- I S-thiazolyl CH, Citrate 5-thiazolyl I-I-- fumarate 4-methyl-5-oxazolyl H-- tartrate 4-methyl-5-thiazolyl CI-I,- acetate 4-isothiazolyl Cl-I, acetate 3-methyl-4-isothiazolyl H- succinate 3-pyrazolyl CI-I, Cl- 3-pyramlyl Br Z-pyrrolyl CH, I 2-pyrrolyl H monostearyl fumarate l-methyl-Z-pyroolyl H- l' 4-methyl-3-pyrazolyl H Cl- 3-methyl-4-pyrazolyl CH,- Br 4-isothiazolyl H- Br 4-methyl-5-oxazolyl CH, Cl lmethyl-2-pyrrolyl CH, Cl 4-methyl-5-thiazolyl H- Br 3-methyl-4-isothiazolyl CH, Br 4-methyl-3-pyrazolyl CH,-- Cl 3-methyl-4-pyrazolyl H- I EXAMPLE XIX l-[2-(2MethyI-3-thienyl)vinyl] pyridinium Bromide A. Methyl 2-Methyl-3-thienyl Ketone Under a nitrogen atmosphere, a solution of one mole of 3-bromo-2-methylthiophene in 500 ml. of dry diethyl ether is allowed to react with one gram-atom of magnesium tumings until the metal dissolves. A crystal of iodine is added to initiate the reaction. The resulting solution is then added dropwise with efficient stirring to a solution of 5 moles of ethyl acetate and 500 ml. of dry diethyl ether which is maintained at C. by means of a dry ice/acetone bath. After the addition is complete, the solution is allowed to warm to room temperature, and is then heated under reflux for 2 hours. Ether is distilled from the mixture and the residue is taken up in ml. benzene. After cooling in an ice bath, the solution is cautiously treated with 200 ml. of water and then with ml. of 6N hydrochloric acid. Stirring is continued until all the precipitate dissolves. The organic layer is separated, and the aqueous layer is extracted several times with benzene. The combined organic phases are then evaporated under reduced pressure, and the residue is fractionally distilled to yield methyl 2-methyl-3-thienyl ketone.

B. Following the procedure of Example I, parts A, B and C, l-[2-( 2-methyl-3-thienyl)vinyl] pyridinium bromide is prepared from methyl 2-methyl-3-thienyl ketone.

EXAMPLE XX 1 -[2-( 3-halo-2-thienyl )vinyl ]pyridinium Bromides A. The l-( 3-halo-2-thenoylmethyl)pyridinium bromides, where halo is chloro, bromo or iodo, are prepared according to the procedure of Example I part A starting with the following methyl ketones:

Methyl Ketones 3-chloro-2-thienyl Reference E. Profft and G. Solf,

J. prakt. Chem. 24,38 (I964) Steinkopf, Jacob and Penz, Ann. 152,136 (1934) 3-bromo-2-thienyl 3-iodo-2-thienyl S. Gronowitz and L.

Karlsoon, Acla Chem.

Scand. 17,2120 (I963) Karlsson,

B. The l-[2-hydroxy-2(3--halo-2-thienyl)ethyl] pyridine.

EXAMPLE XXI l-( 2-Ethylstyryl )pyridinium Bromide When in the procedure of Example I, part A, methyl 2-ethylphenyl ketone prepared according to the procedure of R. Riemschneider and HG. Kassahn, Ber. 92, 1705(1959), is substituted for methyl 3-methyl-2- thienyl ketone, l-(Z-ethyIphenacyDpyridinium bromide is obtained.

In a similar manner, following the procedures of Example I, parts B and C, l-(B-hydroxy-2- ethylphenethyl)pyridinium bromide and l-(2-ethylstyryl) pyridinium bromide are obtained.

EXAMPLE XXII l-[ 2 3-Ethyl-2-thienyl)vinyl]pyridinium Bromide When in the procedure of Example I, pan A, methyl 3-ethyl-2-thienyl ketone [Gerlach, Ann.267, l53(l882)]cis substituted for methyl 2-methyl-2-thienyl ketone, l-(3-ethyl-2-thenoylmethyl)pyridinium bromide is obtained.

In a similar manner, and following the procedures of Example I, parts Band C, l-[2-hydroxy-2-( 3-ethyl-2- thienyl)ethyl]pyridinium bromide and l-[2-( 3-ethyl-2- thienyl)vinyl]pyridinium bromide, are obtained.

EXAMPLE XXIII l-[2-( 3-Methyl-2-furyl)vinyl] pyridinium Bromide When in the procedure of Example I, part A, methyl 3-methyl-2-furyl ketone is substituted for methyl 3- methyl-2-thienyl ketone, l( 3-methyl-2furoyl methyl) pyridinium bromide is obtained.

In a similar manner, following the procedures of Example I, parts B and C, l -[2-hydroxy-2-(3-methyl-2-furyl)ethyl] pyridinium bromide and l-[2-(3-methyl-2- furyl)vinyl]pyridinium bromide are obtained.

EXAMPLE XXIV When the procedure of Example XIII is applied to the compounds of Table VIII, the compounds are found to be effective anthelmintic agents.

TABLE vm l-( 3-chloro-2-thenoylmethyl )pyridinium bromide l-( 3-bromo-2-thenoylmethyl)pyridinium bromide l 3-iodo-2-thenoylmethyl )pyridinium bromide When the procedure of Example I is repeated, substituting for methyl 3-methyl-2-thienyl ketone a methyl aryl ketone where aryl is 3-thienyl, 2-furyl, 3-furyl, phenyl, 2-methylphenyl, Z-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-chlorophenyl, 2- bromophenyl, 2-iodophenyl or 2-fluorophenyl, the corresponding keto intermediates, the 2-hydroxyethyl intermediates and the vinyl products are formed.

What is claimed is:

l. A quaternary ammonium compound selected from the group consisting of those having the formula:

where Y is 2-thiazolyl, 4-thiazolyl, S-thiazolyl, 4- isothiazolyl, 4-methyl-5-thiazolyl, 3-methyl-4- isothiazoly], 3-pyrazolyl, 4-methyl-3-pyrazolyl, 3- methyl-4-pyrazolyl, 4-methyl-5-oxazolyl,- 2-pyrrolyl, lmethyl-Z-pyrrolyl, 3-halo-2-thienyl where halo is chloro, bromo or iodo; R is hydrogen or methyl; and X is a pharmacologically-acceptable anion.

@1330 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTiON 3, 0 August 15, 1972 Patent No. Dated James W. McFarland It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

F601. 2, line 42, after "2-furyl," insert 3-furyl, 7

,Col. 8, l'able I, second heading, "l -(2-a cylvinyl pyridinium bromide" should read l-(2-arylvinyl)pyridinium bromide iCol. 15, last structure in first Ar column,

CH OH H i 2 v should read i i 3 3;-methyl-2-thienyl V 3-methyl-2-thienyl Col. 16, first structure in first Ar column,

. H N on 1 5| 3 i should read t H 3 3 y 5- y r 4-methyl-5-thiezolyl second structure in first Ar column, .l

" I i I should read I g S Y 3H- v C 3 d 3 'l- -methyl-2-pyrrolyll-methyl-Q-pyrrolylthird stz 'ucture 'in'second Ar column,

on r CH 3 g I should read I 3 niethyl- 4-pyrazolyl 3-methyl-4-pyrazolyl L Signed and sealed this 3rd day of July 1973.

(SEAL) I Attest:

EDWARD M.PLETCHER,JR. Rene Tegtmeyer Attestiug Officer Acting Commissioner of Patents 

